👤 V Adámková

High plasma levels of triglycerides (TG) are an independent risk factor in the development of cardiovascular disease, with about 50 % of the final levels being determined genetically. Apolipoprotein A5 (APOA5) is the last discovered member of the apolipoprotein APOA1/C3/A4 gene cluster, found by comparative sequencing analysis. The importance of APOA5 gene for determination of plasma triglyceride levels has been suggested after development of transgenic and knock-out mice (transgenic mice displayed significantly reduced TG, whereas knock-out mice had high TG). In Czech population, alleles C-1131 and Trp19 are associated with elevated levels of plasma TG and higher risk of myocardial infarction development. These alleles also play some role in nutrigenetics and actigenetics of lifestyle interventions leading to the plasma cholesterol changes as well as in the pharmacogenetics of statin treatment. On the contrary, APOA5 mutations detected in Czech population did not show strict effect on plasma TG levels. Val153 --> Met variant exhibit the sex-specific effect of HDL-cholesterol levels. The suggested roles of APOA5 variants in determination of the plasma remnant particles, plasma concentrations of C-reactive protein or some anthropometrical parameters were excluded. Show less

The importance of the apolipoprotein A5 (APOA5) gene in determining plasma triglyceride (TG) levels has been demonstrated in transgenic and knockout mice and confirmed by human association studies in different ethnic groups. We screened for nonsynonymous APOA5 mutations in patients with plasma TG levels >10 mmol/L. The coding sequence and promoter region of the APOA5 gene were sequenced in 95 individuals with severe hypertriglyceridemia (HTG). A large population sample of 3,202 individuals was screened by PCR and restriction analysis for presence of detected mutation. In total, three heterozygous carriers of 944C>T (Ala315>Val) were identified in the severe HTG patients, while 22 carriers were identified in the population sample. The rare allele frequency of the Val315 was significantly higher in the HTG sample than in controls (0.016 vs. 0.003, p<0.01, respectively). Most of the control Ala315Val carriers, however, had plasma lipid levels (TGs, total cholesterol and high-density lipoprotein cholesterol) within the usual range detected in the population. APOA5 Ala315>Val does not play any dominant/important role in the genetic determination of plasma TG levels, but the increased frequency in HTG patients compared to controls suggests that it might interact with other gene variants to cause HTG. Show less

The APOA5 and APOE genes play an important role in determination of plasma levels of triglycerides (TG) and total cholesterol (TC). We have analyzed APOA5 (T-1131>C and Ser19>Trp) and APOE (e2/e3/e4) variants in 2500 representatively selected Caucasians (1168 men, 1332 women). In female subjects (but not in male) an association between APOE polymorphism and TC was observed on the background of the common APOA5 haplotype (TT-1131/SerSer19) - APOE2 carriers have the lowest (5.12 (1.15) mmol/l) and the APOE4 carriers have the highest (6.05 (1.06) mmol/l) levels of plasma TC (P<0.001). If at least one APOA5 C-1131 or Trp19 allele was present, APOE exhibits no significant effect on plasma TC. APOA5 did not affect plasma TG levels, if APOE4 allele was present. In the presence of APOE2 or APOE3, carriers of the APOA5 alleles, C-1131 and/or Trp19, have higher TG levels (1.64 (1.05) mmol/l) than others (1.37 (0.75) mmol/l) (P<0.01). In male subjects, the same, but non-significant trend was observed. In female subjects, we have detected an interaction between APOE and APOA5 variants and plasma lipid levels. Show less

The apolipoprotein A-V (apo A-V) plays an important role in regulation of triglyceride (TG) concentration in serum. To better understand how apo A-V affects triglyceridemia and glucoregulation, the lipoprotein lipase (LPL) activity was determined using intravenous fat tolerance test (IVFTT) and oral glucose tolerance test (oGTT) was performed in carriers of apolipoprotein A-V gene (APOAV) variants known to be associated with increased triglyceridemia. Twelve carriers of 19W variant, 16 carriers of -1131C variant, 1 combined heterozygote and 16 control subjects homozygous for wild type variants (19S/-1131T) were selected from a population sample and matched with respect to body mass index and age. The APOAV variants carriers had increased TG, very low density lipoprotein-TG, and apo B concentrations (p < 0.05). The LPL activity evaluated as k(2) rate constant for clearance of Intralipid was 14 % lower in APOAV variants carriers. The depression of nonesterified fatty acids (NEFA) concentration after glucose load was delayed in APOAV variants carriers in spite of the same insulinemia and glycemia. Our results suggest that variants of APOAV combined with increased triglyceridemia are associated with lower LPL activity in vivo and with disturbances of regulation of NEFA concentration after glucose load. Show less

To evaluate whether the relationship between dietary composition and plasma lipid levels is genetically determined. We have evaluated the influence of common apolipoprotein A5 (APOA5) variants (T-1131 > C, Ser19 > Trp and Val153 > Met) on plasma lipid concentrations in 117 males for whom dietary composition markedly changed and total cholesterol decreased (from 6.21 +/- 1.31 mmol/L in 1988 to 5.43 +/- 1.06 mmol/L in 1996) over an 8 year follow-up study. APOA5 T-1131 > C and Val153 > Met variants did not influence the change in lipid measures over time. In Ser/Ser19 homozygotes, the plasma cholesterol was relatively stable over the years (6.1 +/- 1.2 mmol/L in 1988 and 5.6 +/- 1.0 mmol/L in 1996, -8%, P < 0.01). In contrast, in the Trp19 carriers, the decrease of the plasma cholesterol was more than 20% (6.5 +/- 1.6 mmol/L in 1988 and 5.1 +/- 1.0 mmol/L in 1996) (P < 0.001). The difference of the changes is significant (8% vs. 20%, P < 0.005). Changes in other analyzed lipid parameters have not been significantly associated with APOA5 variants. Ser19 > Trp variant in the APOA5 gene may play an important role in an individual's sensitivity to dietary composition. Show less

The importance of the APOAV gene for the determination of plasma triglyceride levels has been suggested by creations of transgenic and knockout mice and confirmed in population studies. We examined whether the newly detected APOAV variant is associated with plasma lipid levels and risk of myocardial infarction (MI). APOAV polymorphism (Val153>Met) was genotyped in 1191 males and 1368 females representatively selected from the Czech population. Lipid levels were analyzed in 1997 and 2001 in all individuals. Subsequently, we have analyzed the genotype frequencies of APOAV polymorphism in 435 male patients with MI. Val153>Met variation in the APOAV gene affects the plasma high-density lipoprotein cholesterol levels showing a higher level in Val/Val homozygotes than in Met carriers in both years (1.51 +/- 0.36 and 1.52 +/- 0.37 mmol/L compared with 1.42 +/- 0.33 and 1.39 +/- 0.35 mmol/L, P < .01). This association has been observed in females but not in males. Other analyzed lipid parameters (total cholesterol, low-density lipoprotein cholesterol, and triglycerides) have not been associated with APOAV Val153>Met variant. In a group of patients with MI, the frequency of the Met153 carriers was not significantly different from the male population sample (6.5% vs 6.4%). Val153>Met variation in the APOAV gene plays a sex-specific role in genetic determination of plasma high-density lipoprotein cholesterol levels, but does not influence risk of MI in males. Show less

The important role of APOAV gene variants in determination of plasma triglyceride levels has been shown in many population studies. Recently, an influence of APOAV T-1131>C polymorphism on C-reactive protein (CRP) in young Korean males has been reported. We have therefore analyzed a putative association between T-1131>C, Ser19>Trp and Val153>Met APOAV variants (PCR and restriction analysis) and CRP concentrations in 1119 Caucasian males, aged between 28 and 67 years (49.2+/-10.8 years). The frequency of C allele carriers was lower in Caucasians than in Koreans (15.5% vs. 46.2%). CRP levels did not differ between T/T homozygotes (n=946, 1.61+/-2.05 mg/l) and carriers of the C allele (n=173, 1.67+/-1.95 mg/l). Thus, in contrast to Korean males, T-1131>C APOAV variant has no effect on plasma concentrations of CRP in a large group of Caucasian males. Other APOAV variants (Ser19>Trp and Val153>Met) did not also influence plasma concentrations of CRP. APOAV variants are unlikely to be an important genetic determinant of plasma CRP concentrations in Caucasian males. Show less

Animal studies (on transgenic and knock-out mice) and human association analysis assessed the importance of APOAV gene for plasma triglyceride determination. New APOAV missense variants (Val153 --> Met and Cys185 --> Gly) have been detected recently. We have analyzed these variants in 83 unrelated patients with extreme lipid parameters (triglycerides of 20.4+/-2.8 mmol/l and total cholesterol of 10.4+/-3.7 mmol/l) and in a control population group consisting of 2,559 unrelated Caucasians. In patients, the frequency of the Met153 carriers was slightly but not significantly higher (9.64 % vs. 6.49 %) compared to the population sample. This suggested that Val153 Met polymorphism in the APOAV gene does not represent an important risk factor for developing the extreme levels of plasma triglycerides. We did not detect carriers of the Gly185 allele among patients or 420 healthy individuals. We suppose that this variant is probably not present in Caucasian populations Show less

The importance of an APOAV gene for plasma triglyceride level determination has been shown on transgenic and knockout mice. We examined whether APOAV variants are associated with plasma triglyceride levels and risk of myocardial infarction (MI). We have evaluated the influence of APOAV polymorphisms (T-1131>C and S19>W) on plasma triglycerides in 1191 males and 1368 females representatively selected from the Czech population. Triglycerides have been analysed in 1997 and 2001. Subsequently, we have analysed the genotype frequencies of the APOAV polymorphism in 435 patients with MI. T-1131>C variation in the APOAV gene affects the plasma triglyceride showing a higher level in C-1131 carriers than in T/T-1131 homozygotes. This association has been observed both in males and females (p < 0.001). Similarly, plasma triglycerides were also significantly influenced by the S19>W APOAV genotypes. In both males and females, the W19 carriers have triglycerides significantly (p < 0.001) higher compared to the S19 homozygotes. In a group of MI patients, the frequency of the rare homozygotes for at least one APOAV polymorphism (C/C-1131 and/or W/W19) was significantly higher than that in the population sample (7.4 vs 2.0%, p < 0.00001). We conclude that variations in the APOAV gene not only play a role in genetic determination of triglyceride levels but also could influence risk of MI. Show less